Action Points

Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Note that this randomized trial of a novel biologic agent suggests efficacy in the treatment of refractory ulcerative colitis.

WASHINGTON -- Clinical response rates of up to 54% were seen with a new type of biologic drug in ulcerative colitis patients with moderately to severely active disease who had failed at least one prior therapy, a researcher reported here.

Up to 17% had complete clinical remission and, with the optimum dose, 28% showed mucosal healing with the drug, currently known as PF-00547659, said Walter Reinisch, MD, of McMaster University Health Centre in Hamilton, Ontario.

All primary and secondary endpoints were met in the Pfizer-sponsored phase II trial called TURANDOT, Reinisch told attendees at a late-breaking clinical trials session at the Digestive Disease Week annual meeting.

The drug is among several that target white blood cell trafficking in the intestinal mucosa as a means of treating inflammatory bowel disease. Key to this trafficking is the alpha4beta7 integrin protein carried on leukocytes; the currently approved ulcerative colitis drug vedolizumab (Entyvio) and an investigational agent for the condition called etrolizumab both bind to this molecule, as does the multiple sclerosis drug natalizumab (Tysabri).

But the experience with natalizumab, which promotes an often fatal brain inflammation known as progressive multifocal leukoencephalopathy (PML), has made gastroenterologists wary of agents sharing any aspect of its mechanism of action. Although no cases of PML have been seen so far with the other anti-alpha4beta7 agents, the FDA questioned vedolizumab's developer closely about the risk before approving the drug.

In part to circumvent such concerns, the Pfizer drug targets a different factor called MAdCAM-1, an adhesion molecule on endothelial cells that interacts with alpha4beta7. Reinisch said the drug -- unlike natalizumab -- has no effect on immune surveillance in the central nervous system and does not bind to VCAM-1, another indirect target of natalizumab that appears to be involved in PML.

For the phase II TURANDOT study, Reinisch and colleagues enrolled 357 patients with refractory, active ulcerative colitis and randomized them to placebo or one of four doses of PF-00547659: 7.5, 22.5, 75, and 225 mg, administered every 4 weeks, with endpoints assessed after 12 weeks.

A significant difference from placebo in rates of clinical remission, defined as a Mayo score of 2 or less at week 12, was the trial's primary endpoint. Secondary endpoints included rates of clinical response (decrease in total Mayo score of at least 3 points or decrease in rectal bleeding subscore by greater than 30% or an absolute subscore of 1 or less), mucosal healing (endoscopy subscore of 1 or less), other levels of decrease in Mayo score, and change from baseline in fecal calprotectin.

A consistent finding for all these endpoints was that the 22.5-mg dose was the most effective, at the zenith of a bell-shaped dose-response curve. The least effective dose for most outcomes was 225 mg, with the 7.5-mg dose usually the second-least effective.

Major efficacy results with the 22.5-mg dose and placebo in a modified intent-to-treat analysis were as follows (all P<0.05):

Clinical remission: 16.7% drug, 2.7% placebo

Clinical response: 54.2% drug, 28.8% placebo

Mucosal healing: 27.8% drug, 8.2% placebo

Reinisch noted that patients who had previously failed an anti-tumor necrosis factor agent had poorer responses than those who had not received such drugs, with remission rates of 9.8% versus 25.8% for the 22.5-mg dose of PF-00547659.

He also reported that fecal calprotectin levels declined by about the same degree with all doses of the drug, whereas there was no change with placebo.

Safety findings were mostly unremarkable. Overall and serious adverse event rates were similar between the placebo and all active-drug groups, with no obvious dose-response relationship with the drug for any of the events tracked. Reinisch made special mention of the similarity among all groups, including placebo, in rates of infections outside the GI tract in tissues known to express the MAdCAM target.

A total of nine patients (3%) across all the active-drug groups discontinued because of adverse effects, compared with two (3%) in the placebo group.

Accessibility Statement

At MedPage Today, we are committed to ensuring that individuals with disabilities can access all of the content offered by MedPage Today through our website and other properties. If you are having trouble accessing www.medpagetoday.com, MedPageToday's mobile apps, please email legal@ziffdavis.com for assistance. Please put "ADA Inquiry" in the subject line of your email.